Parathyroid hormone (PTH) is a systemic calcium-regulating hormone with catabolic and anabolic effects in bone. A fragment of PTH containing the first 34 amino acids (1-34) is currently under investigation for its potential as a therapeutic agent to treat metabolic bone disease; however, its mechanism of action is not known. In vivo studies indicate that the N-terminus of PTH is necessary, and an intermittent regime of dosage is optimal, for PTH-mediated bone formation. One hypothesis is that PTH acts on osteoblasts in an indirect manner to cause them to produce "osteoblast-activating" factor(s) responsible for recruiting precursor cells to differentiate into active osteoblasts and form bone. Initial studies are underway to identify the pathways operative in this process. Data from the Principal Investigator's laboratory, and others in the field, indicate that N-terminus PTH activates its cell surface receptor, and stimulates the proto-oncogene c-fos in a manner which is dependent upon activation of protein kinase A. The overall goal of this application is to determine whether the signaling pathway through cAMP and c-fos is necessary for anabolic actions of PTH in bone. The specific hypothesis is that a functional PTH-1 (PTH/PTHrP) receptor which signals through the cAMP pathway via the cAMP response element binding protein, and stimulation of c-fos are necessary for PTH-mediated anabolic effects in bone. In vitro models of genetically altered undifferentiated mesenchymal cells, an in vivo diffusion chamber model, and an in vivo gene therapy osteotomy model will be utilized to test the hypothesis. These studies will provide information critical for understanding how PTH acts to stimulate bone formation and will provide the basis for rational design of therapies to treat metabolic bone disease.